Cholesterol And Sterol Metabolism
DR MUHAMMAD MUSTANSAR
Lipid metabolism
Cholesterol Functions
• Membrane component

• Precurser to
– Bile acids

– Vitamin D
– Steroid hormones
Central Role of the liver in Cholesterol Balance:
Sources of hepatic cholesterol
• Dietary cholesterol
– From chylomicron ...
Central Role of the liver in Cholesterol Balance:
Fate of hepatic cholesterol
• VLDL -> LDL
– Transport to extra-hepatic t...
De novo Synthesis of Cholesterol
• Primary site: liver (~1g/d)
– Secondary sites: adrenal cortex, ovaries, testes

• Overa...
Hydroxymethylglutaryl-coenzyme A (HMG-CoA)
is the precursor for cholesterol synthesis.
HMG-CoA is also an intermediate on ...
 HMG-CoA is formed by condensation of acetyl-CoA
& acetoacetyl-CoA, catalyzed by HMG-CoA
Synthase.
 HMG-CoA Reductase ca...
De novo Synthesis of
Cholesterol: four stages
• Formation of HMG CoA (cyto)
– Analogous to KB synthesis (mito)

• Conversi...
De novo Synthesis of
Cholesterol: four stages

• Condensation of isoprenoids to squalene
– Six isoprenoids condense to for...
De novo synthesis of
Cholesterol: four stages
• Conversion of Squalene to Cholesterol
De novo Synthesis of Cholesterol:
What do you need to know?
• All carbons from acetyl-CoA

• Requires NADPH, ATP, & O2
• S...
Regulation of Cholesterol
Synthesis
• Cellular cholesterol content exerts transcriptional

control
– HMG-CoA reductase
• H...
Regulation of Cholesterol
Synthesis
• Covalent Modification of HMG-CoA Reductase
– Insulin induces protein phosphatase
– A...
Regulation of Cholesterol Synthesis
• Covalent Modification of HMG-CoA
Reductase
– Glucagon stimulates adenyl cyclase prod...
Cholesterol and Bile Acid / Salt Metabolism
• Major excretory form of cholesterol
– Steroid ring is not degraded in humans...
Types of Bile Acids / Salts
• Primary bile acids
– Good emulsifying agents
• All OH groups on same side
• pKa = 6 (partial...
Synthesis of Bile Salts
• Hydroxylation
– Cytochrome P-450/mixed function oxidase system

• Side chain cleavage
• Conjugat...
• Secondary bile acids
– Intestinal bacterial modification
• Deconjugation
• Dehydroxylation
– Deoxycholic acid
– Lithocho...
Recycling of Bile Acids
• Enterohepatic circulation
– 98% recycling of bile acids

• Cholestyramine Treatment
– Resin bind...
Plant stanols
No double bond on B ring

Plant sterols
Different side chains
Structures of
Common statin
drugs
Statin drugs are structural analogs of
HMG-CoA
Case Study
-familial hypercholesterolemia
• 8 yo girl
– Admitted for heart/liver transplant

• History
– CHD in family

– ...
– 7 yo admitted w/ MI symptoms
• [TC] = 1240 mg/dl
• [TG] = 350 mg/dl
• [TC]father = 355 mg/dl
• [TC]mother = 310 mg/dl
– 2 wks after MI had coronary bypass surgery
– Past year severe angina & second bypass
– Despite low-fat diet, cholestyram...
Xanthomas
• Raised, waxy appearing,

often yellow skin lesions
(shown here on knee)
– Associated with hyperlipidemia

• Te...
Xanthomas
Raised lesions related to hyperlipidemia

Eruptive Xanthomas
-generally associated with
hypertriglyceridemia

Xa...
Did Da Vinci’s
Mona Lisa have
hyper-cholesterolemia ?
Steroid Hormone Metabolism:
Adrenal Steroid Hormones
• Aldosterone
– C21 derivative of cholesterol
– Promotes renal
• Sodi...
• Glucocorticoids (cortisol)
– Starvation
• Hepatic gluconeogenesis
• Muscle protein degradation
• Adipose lipolysis

• Ad...
Cholesterol metabolism
Cholesterol metabolism
Cholesterol metabolism
Cholesterol metabolism
Cholesterol metabolism
Cholesterol metabolism
Cholesterol metabolism
Cholesterol metabolism
Cholesterol metabolism
Cholesterol metabolism
Cholesterol metabolism
Cholesterol metabolism
Cholesterol metabolism
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Cholesterol metabolism

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Transcript of "Cholesterol metabolism"

  1. 1. Cholesterol And Sterol Metabolism DR MUHAMMAD MUSTANSAR
  2. 2. Lipid metabolism
  3. 3. Cholesterol Functions • Membrane component • Precurser to – Bile acids – Vitamin D – Steroid hormones
  4. 4. Central Role of the liver in Cholesterol Balance: Sources of hepatic cholesterol • Dietary cholesterol – From chylomicron remnants • Cholesterol from extra-hepatic tissues – Reverse cholesterol transport via HDL • Chylomicron remnants • IDL • De novo synthesis
  5. 5. Central Role of the liver in Cholesterol Balance: Fate of hepatic cholesterol • VLDL -> LDL – Transport to extra-hepatic tissues • Direct excretion into bile – Gallstones commonly are precipitates of cholesterol • Occurs when bile becomes supersaturated with cholesterol – Obesity, biliary stasis, infections • Bile acid synthesis and excretion into bile
  6. 6. De novo Synthesis of Cholesterol • Primary site: liver (~1g/d) – Secondary sites: adrenal cortex, ovaries, testes • Overall equation:
  7. 7. Hydroxymethylglutaryl-coenzyme A (HMG-CoA) is the precursor for cholesterol synthesis. HMG-CoA is also an intermediate on the pathway for synthesis of ketone bodies from acetyl-CoA. The enzymes for ketone body production are located in the mitochondrial matrix. HMG-CoA destined for cholesterol synthesis is made by equivalent, but different, enzymes in the cytosol.
  8. 8.  HMG-CoA is formed by condensation of acetyl-CoA & acetoacetyl-CoA, catalyzed by HMG-CoA Synthase.  HMG-CoA Reductase catalyzes production of mevalonate from HMG-CoA.
  9. 9. De novo Synthesis of Cholesterol: four stages • Formation of HMG CoA (cyto) – Analogous to KB synthesis (mito) • Conversion of HMG CoA to activated isoprenoids
  10. 10. De novo Synthesis of Cholesterol: four stages • Condensation of isoprenoids to squalene – Six isoprenoids condense to form 30-C molecue
  11. 11. De novo synthesis of Cholesterol: four stages • Conversion of Squalene to Cholesterol
  12. 12. De novo Synthesis of Cholesterol: What do you need to know? • All carbons from acetyl-CoA • Requires NADPH, ATP, & O2 • Stages – One: forms HMG CoA – Two: forms activated 5 carbon intermediates (isoprenoids) – Three: six isoprenoids form squalene – Four: squalene + O2 form cholesterol
  13. 13. Regulation of Cholesterol Synthesis • Cellular cholesterol content exerts transcriptional control – HMG-CoA reductase • Half life = 2 hours – LDL-receptor synthesis • Nutrigenomics: – interactions between environment and individual genes and how these interactions affect clinical outcomes
  14. 14. Regulation of Cholesterol Synthesis • Covalent Modification of HMG-CoA Reductase – Insulin induces protein phosphatase – Activates HMG-CoA reductase • Feeding promotes cholesterol synthesis – Activates reg. enzyme – Provides substrate: acetyl CoA – Provides NADPH
  15. 15. Regulation of Cholesterol Synthesis • Covalent Modification of HMG-CoA Reductase – Glucagon stimulates adenyl cyclase producing cAMP – cAMP activates protein kinase A – Inactivates HMG-CoA reductase • Fasting inhibits cholesterol synthesis
  16. 16. Cholesterol and Bile Acid / Salt Metabolism • Major excretory form of cholesterol – Steroid ring is not degraded in humans – Occurs in liver • Bile acid/salts involved in dietary lipid digestion as emulsifiers
  17. 17. Types of Bile Acids / Salts • Primary bile acids – Good emulsifying agents • All OH groups on same side • pKa = 6 (partially ionized) • Conjugated bile salts – Amide bonds with glycine or taurine – Very good emulsifier • pKa lower than bile acids
  18. 18. Synthesis of Bile Salts • Hydroxylation – Cytochrome P-450/mixed function oxidase system • Side chain cleavage • Conjugation
  19. 19. • Secondary bile acids – Intestinal bacterial modification • Deconjugation • Dehydroxylation – Deoxycholic acid – Lithocholic acid
  20. 20. Recycling of Bile Acids • Enterohepatic circulation – 98% recycling of bile acids • Cholestyramine Treatment – Resin binds bile acids – Prevents recycling – Increased uptake of LDL-C for bile acid synthesis
  21. 21. Plant stanols No double bond on B ring Plant sterols Different side chains
  22. 22. Structures of Common statin drugs
  23. 23. Statin drugs are structural analogs of HMG-CoA
  24. 24. Case Study -familial hypercholesterolemia • 8 yo girl – Admitted for heart/liver transplant • History – CHD in family – 2 yo xanthomas appear on legs – 4 yo xanthomas appear on elbows
  25. 25. – 7 yo admitted w/ MI symptoms • [TC] = 1240 mg/dl • [TG] = 350 mg/dl • [TC]father = 355 mg/dl • [TC]mother = 310 mg/dl
  26. 26. – 2 wks after MI had coronary bypass surgery – Past year severe angina & second bypass – Despite low-fat diet, cholestyramine, & lovastatin, [TC] = 1000 mg/dl
  27. 27. Xanthomas • Raised, waxy appearing, often yellow skin lesions (shown here on knee) – Associated with hyperlipidemia • Tendon xanthomas common on Achilles and hand extensor tendons
  28. 28. Xanthomas Raised lesions related to hyperlipidemia Eruptive Xanthomas -generally associated with hypertriglyceridemia Xanthomas of the eyelid -generally associated with hypercholesterolemia
  29. 29. Did Da Vinci’s Mona Lisa have hyper-cholesterolemia ?
  30. 30. Steroid Hormone Metabolism: Adrenal Steroid Hormones • Aldosterone – C21 derivative of cholesterol – Promotes renal • Sodium retention • Potassium excretion
  31. 31. • Glucocorticoids (cortisol) – Starvation • Hepatic gluconeogenesis • Muscle protein degradation • Adipose lipolysis • Adrenal androgens – Dehydroepiandroterone (DHEA) • Precurser to potent androgens in extra-adrenal tissues

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